2-(heterocyclylheteroaryliumalkyl) phenyl carbapenem antibacterial agents

ABSTRACT

Carbapenems having the formula:   &lt;IMAGE&gt; (I.)  are useful antibacterial agents.

This is a continuation of application Ser. No. 07/741,183, filed Jul.29, 1991, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to antibacterial agents of the carbapenemclass, in which the 2-position sidechain is characterized by a phenylmoiety, optionally substituted, to which is attached, usually through analkyl bridge, a nitrogen-containing heteroarylium group, with attachmentbeing through the nitrogen atom, to which is attached, in turn, aheterocyclic group, as described in more detail further below.

Thienamycin was an early carbapenem antibacterial agent having a broadspectrum; it has the following formula: ##STR2## Later, N-formimidoylthienamycin was discovered; it has the formula: ##STR3##

The 2-(heterocyclylheteroaryliumalkyl)phenyl carbapenems of the presentinvention have an antibacterial potency equal to or greater than, inmost cases, that of either thienamycin or N-formimidoyl thienamycin. Thecompounds of the present invention are also more resistant thanthienamycin or N-formimidoyl thienamycin to degradation by thedehydropeptidase enzyme DHP-I, thus permitting greater therapeuticapplication of the compounds.

More recently, carbapenem antibacterial agents have been described whichhave a 2-substituent which is an aryl moiety optionally substituted by,e.g., aminomethyl and substituted aminomethyl. These agents aredescribed in U.S. Pat. Nos. 4,543,257 and 4,260,627 and have theformula: ##STR4##

However, these compounds belong to a different class from those of thepresent invention and are distinguished by different physiologicalproperties.

SUMMARY OF THE INVENTION

The present invention provides novel carbapenem compounds of theformula: ##STR5## wherein: R is H or CH₃ ;

R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂ CH--, HOCH₂--, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂ CHCH(OH)--, F₃CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;

R^(a), R^(b), R^(c), and R^(d) are independently selected from the groupconsisting of (R^(c) represents from 1 to 3 substituents which may bethe same or different):

a) a trifluoromethyl group: --CF₃ ;

b) a halogen atom: --Br, --Cl, --F, or --I;

c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl;

d) a hydroxy group: --OH;

e) (C₁ -C₆ alkyl) carbonyloxy radical: ##STR6## alkyl; f) a carbamoyloxyradical which is unsubstituted or substituted on nitrogen with one ortwo C₁ -C₄ aklyl groups: ##STR7## whereby R^(y) and R^(z) areindependently H or C₁₋₄ alkyl; g) a C₁ -C₆ alkylthio radical, C₁ -C₆alkylsulfinyl radical or C₁ -C₆ alkylsulfonyl radical: ##STR8## alkylwhere n=0-2, and the alkyl portion is optionally substituted by cyano;

h) a sulfamoyl group which is unsubstituted or substituted on nitrogenby one or two C₁ -C₄ alkyl groups: ##STR9## where R^(y) and R^(z) are asdefined above; i) an amino group, or a mono (C₁ -C₄ alkyl) amino ordi(C₁ -C₄ alkyl)amino group: ##STR10## where R^(y) and R^(z) are asdefined above; j) a formylamino group: ##STR11## k) (C₁ -C₆alkyl)carbonylamino radical: ##STR12## alkyl; l) a (C₁ -C₄alkoxy)carbonylamino radical: ##STR13## alkyl; m) a ureido group inwhich the terminal nitrogen is unsubstituted or substituted with one ortwo C₁ -C₄ alkyl groups: ##STR14## where R^(y) and R^(z) are as definedabove; n) a sulfonamido group: ##STR15## alkyl; o) a cyano group: --CN;

p) a formyl or acetalized formyl radical: ##STR16## q) (C₁ -C₆alkyl)carbonyl radical wherein the carbonyl is free or acetalized:##STR17## alkyl or ##STR18## alkyl; r) phenylcarbonyl;

s) a hydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: ##STR19## where R^(y)and R^(z) are as defined above; t) a (C₁ -C₆ alkoxy)carbonyl radical:##STR20## alkyl; u) a carbamoyl radical which is unsubstituted orsubstituted on nitrogen by one or two C₁ -C₄ alkyl groups: ##STR21##R^(y) and R^(z) are as defined above; v) an N-hydroxycarbamoyl or N(C₁-C₄ alkoxy)carbamoyl radical in which the nitrogen atom may beadditionally substituted by a C₁ -C₄ alkyl group: ##STR22## where R^(y)and R^(z) are as defined above; w) a thiocarbamoyl group: ##STR23## x)an amidino group ##STR24## where R⁵, R⁶ and R⁷ are independentlyhydrogen, C₁ -C₄ alkyl or wherein two of the alkyl groups together forma C₂ -C₆ alkylidene radical optionally interrupted by a heteroatom andjoined together to form a ring;

y) a carboxamidino group ##STR25## where R⁵, R⁶ and R⁷ are as definedabove; z) a guanidinyl group where R⁶ in a) above is NR⁸ R⁹ and R⁸ andR⁹ are as defined for R⁵ through R⁷ above;

aa) hydrogen;

ab) C₂ -C₆ alkenyl radical;

ac) an unsubstituted or substituted C₂ -C₆ alkynyl radical;

ad) C₃ -C₇ cycloalkyl radical;

ae) C₃ -C₇ cycloalkyl methyl radical;

af) C₅ -C₇ cycloalkenyl radical;

ag) phenyl;

ah) C₁ -C₆ alkyl radical;

ai) C₁ -C₄ alkyl monosubstituted by one of the substituents a)-ag)above;

aj) an anionic function selected from the group consisting of: phosphono[P═O(OM^(c))₂ ]; alkylphosphono {P═O(OM^(c))--[O(C₁ -C₄ alkyl)]};alkylphosphinyl [P═O(OM^(c))--(C₁ -C₄ alkyl)]; phosphoramido[P═O(OMc)N(R^(y))R^(z) and P═O(OM^(c))NHR^(x) ]; sulfino (SO₂ M^(c));sulfo (SO₃ M^(c)); acylsulfonamides selected from the structuresCONM^(c) SO₂ R^(x), CONM^(c) SO₂ N(R^(y))R_(z), SO₂ NM^(c)CON(R^(y))R^(z) ; and SO₂ NM^(c) CN, where

R^(x) is phenyl or heteroaryl, where heteroaryl is as defined belowexcept that there is no quaternary nitrogen and attachment throughnitrogen is optional, and the phenyl and heteroaryl are optionallymono-substituted by R^(q) ; M^(c) is hydrogen or an alkali metal; R^(y)and R^(z) are as defined above; where

R^(q) is a member selected from the group consisting of --OH; --OCH₃ --;--CN; --C(O)NH₂ ; --OC(O)NH₂ ; --OC(O)N(CH₃)₂ ; --SO₂ NH₂ ; --SO₂N(CH₃)₂ ; --SOCH₃ ; --F; --CF₃ ; tetrazolyl; and-COOM^(a), where M^(a)is hydrogen, alkali metal, methyl or phenyl;

A is para (p) or meta (m) with respect to the point of attachment of thephenyl ring to the carbapenem nucleus, and is (CH₂)_(m) --Q--(CH₂)_(n),where m is 0 to 2 and n is 1 or 2; and Q is a covalent bond; O; S; SO;SO₂ ; NH; or N(C₁ -C₄ alkyl); ##STR26## is a monocyclic aromatichydrocarbon group having 5 or 6 ring atoms in which one of the carbonatoms has been replaced by a nitrogen atom and attachment of said groupis by way of said nitrogen atom, and in which one additional carbon atomis optionally replaced by a heteroatom selected from O and S, and from 1to 3 carbon atoms are optionally replaced by a nitrogen heteroatom; and##STR27## is a monocyclic aliphatic hydrocarbon group having 4 to 7 ringatoms in which one of the carbon ring atoms is replaced by a nitrogenatom and attachment of said group is by way of said nitrogen atom to acarbon of the monocyclic aromatic hydrocarbon group described above, andone of the remaining carbon ring atoms is optionally replaced by aheteroatom selected from N, O and S; and wherein the substituent R^(d),defined above, is attached to one of the carbon atoms of the ring; and

Y is selected from:

i) COOH or a pharmaceutically acceptable ester thereof;

ii) COOM wherein M is an alkali metal or other pharmaceuticallyacceptable salt;

iii) COOM wherein M is a negative charge in the case where a permanentpositive charge exists elsewhere in the molecule.

The R^(c).sub.(1-3) substituent represents from 1 to 3 substituentswhich may be the same or different and are selected on an independentbasis. A single such substituent is preferred.

The overall molecule must be electronically balanced. Since a quaternarynitrogen is always present in the compounds of the present invention, abalancing anion must also be present. This is usually accomplished byhaving Y be COO⁻. However, where Y is, e.g., a pharmaceuticallyacceptable ester, a counterion (anion) Z⁻ must be provided, oralternatively, an anionic substituent might be utilized. Further, it iswithin the scope of this invention to utilize an anionic substituentwhere the quaternary nitrogen is already balanced by Y═COO⁻. In thatcase, it will be understood that it is necessary to provide a counterion(cation) for the anionic substituent. However, it is well within theskill of a medicinal chemist, to whom there is available many suitableanionic and cationic counterions, to make such choices.

With reference to the above definitions, "alkyl" means a straight orbranched chain aliphatic hydrocarbon radical.

The term "heteroatom" means N, S, or O, selected on an independentbasis.

Under the definition of "Y", the term "pharmaceutically acceptable esteror salt" refers to those salt and ester forms of the compounds of thepresent invention which would be apparent to the pharmaceutical chemist,i.e., those which are non-toxic and which would favorably affect thepharmacokinetic properties of said compounds, their palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof raw materials, ease of crystallization, yield, stability,hygroscopicity, and flowability of the resulting bulk drug. Since thecompounds of the present invention may be carboxylates, the salts wouldbe cations such as benzathine, chloroprocaine, choline, diethanolamine,meglumine and procaine. The metallic cations such as aluminum, calcium,lithium, magnesium and zinc are potential choices. The alkali metalcations sodium and potassium are specifically defined. It will also benoted that the compounds of the present invention are potentiallyinternal salts or zwitterions, since under physiological conditions thecarboxyl group may be anionic, and this electronic charge will bebalanced off internally against the cationic charge of the heteroaryliumgroup. Where this is not the case, it is recognized that a counterionmust be present. This counterion is selected from the group of suitablepharmaceutical anions, e.g., chloride, phosphate and tartrate.

It is preferred that when one of R¹ or R² is H, the other is (R)--CH₃CH(OH)-- or (R)--CH₃ CH(F)--, and (R)--CH₃ CH(OH)-- is most preferred.Further, it is preferred that the configuration at C-6 is (S), and thatat C-5 is (R).

Representative A groups are --CH₂ --, --CH₂ CH₂ --, and --OCH₂ CH₂ --.Preferred is --CH₂ --.

Representative R^(c) and R^(d) groups are --CH₃, ##STR28## Usefulexamples of the heteroarylium moiety are set out below. Theheteroarylium moiety has been conveniently represented throughout by thefollowing formula: ##STR29## where X=O, S, or NR^(e), where R^(e) =C₁₋₄alkyl, CH₂ SO₃ ⁻, CH₂ CH₂ SO₂ ⁻, or CH₂ COR.sup. f, where R^(f) =OCH₃,OCH₂ -phenyl, NH₂, or O⁻ M⁺, where M⁺ =Na⁺ or K⁺.

The pyridinium group is preferred since it provides the desiredproperties of good antibacterial spectrum and potency combined withchemical stability and satisfactory resistance to hydrolysis by thedihydropeptidase (DHP-I) enzyme, together with ready availability andease of handling as a starting material. However, any of the othergroups set out above, as well as those falling within the definition ofthe heteroarylium moiety set out herein but not specifically describedabove, are also suitable, although perhaps in some cases less desirablein terms of one or more of the criteria mentioned above.

Representative examples of the heterocyclyl moiety are set out below.##STR30## With regard to all of the preferred substituents describedabove, the following compounds are preferred embodiments of the presentinvention: ##STR31## where R' is a negative charge ⁻, or apharmaceutically acceptable salt or ester.

While R=H is usually preferred, there are instances in which R=CH₃ mayprovide improved chemical stability, water solubility, orpharmacokinetic behavior. The substituent R=CH₃ may be of eitherconfiguration, i.e., the α or β-stereoisomer.

For most of the compounds exemplified herein, the R substituent ishydrogen. This is the result not only of a more facile synthesis forsuch compounds, but also of a preference for R=hydrogen based on thesuperior antibacterial activity of such compounds.

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms in thetreatment of bacterial infections in animal and human subjects.Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is also concerned withpharmaceutical compositions and methods of treating bacterial infectionsutilizing as an active ingredient the novel carbapenem compounds of thepresent invention.

The pharmaceutically acceptable salts referred to above includenon-toxic acid addition salts. In those cases where the Formula Icompounds possess a basic functional group, they can be used in the formof salts derived from inorganic or organic acids. Included among suchsalts are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate, and undecanoate.Also, the basic nitrogen-containing groups can be quaternized with suchagents as lower alkyl halides, such as methyl, ethyl, propyl, and butylchloride, bromides and iodides; dialkyl sulfates like dimethyl, diethyl,dibutyl; and diamyl sulfates, long chain halides such as decyl, lauryl,myristyl and stearyl chlorides, bromides and iodides, aralkyl halideslike benzyl and phenethyl bromides and others. Water or oil-soluble ordispersible products are thereby obtained.

The pharmaceutically acceptable esters of the novel carbapenem compoundsof the present invention are such as would be readily apparent to amedicinal chemist, and include, for example, those described in detailin U.S. Pat. No. 4,309,438, Column 9, line 61 to Column 12, line 51,which is incorporated herein by reference. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and those described in detail inU.S. Pat. No. 4,479,947, which is incorporated herein by reference.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and Gram-negative bacteria andaccordingly find utility in human and veterinary medicine.Representative pathogens which are sensitive to the antibacterial agentsof the present invention include various species or strains of thefollowing: Staphylococcus, Enterococcus, Escherichia coli, Klebsiella,Enterobacter, Bacillus, Salmonella, Pseudomonas, Serratia, Proteus, andBacterium. The antibacterials of the invention are not limited toutility as medicaments; they may be used in all manner of industry, forexample: additives to animal feed, preservation of food, disinfectants,and in other industrial systems where control of bacterial growth isdesired. For example, they may be employed in aqueous compositions inconcentrations ranging from 0.1 to 100 parts of antibiotic per millionparts of solution in order to destroy or inhibit the growth of harmfulbacteria on medical and dental equipment and as bactericides inindustrial applications, for example in waterbased paints and in thewhite water of paper mills to inhibit the growth of harmful bacteria.

The compounds of this invention may be used in any of a variety ofpharmaceutical preparations. They may be employed in capsule, powderform, in liquid solution, or in suspension. They may be administered bya variety of means; those of principal interest include: topically orparenterally by injection (intravenously or intramuscularly).

Compositions for injection, a preferred route of delivery, may beprepared in unit dosage form in ampules, or in multidose containers. Thecompositions may take such forms as suspensions, solutions, or emulsionsin oily or aqueous vehicles, and may contain formulatory agents.Alternatively, the active ingredient may be in powder form forreconstitution, at the time of delivery, with a suitable vehicle, suchas sterile water. Topical applications may be formulated in hydrophobicor hydrophilic bases as ointments, creams, lotions, paints, or powders.

The dosage to be administered depends to a large extent upon thecondition and size of the subject being treated as well as the route andfrequency of administration, the parenteral route by injection beingpreferred for generalized infections. Such matters, however, are left tothe routine discretion of the therapist according to principles oftreatment well known in the antibacterial art. In general, a dailydosage consists of from about 5 to about 600 mg of active ingredient perkg of body weight of the subject in one or more treatments per day. Apreferred daily dosage for adult humans lies in the range of from about10 to 240 mg of active ingredient per kg of body weight. Another factorinfluencing the precise dosage regimen, apart from the nature of theinfection and peculiar identity of the individual being treated, is themolecular weight of the chosen species of this invention.

The compositions for human delivery per unit dosage, whether liquid orsolid, may contain from 0.1% to 99% of active material, the preferredrange being from about 10-60%. The composition will generally containfrom about 15 mg to about 1500 mg of the active ingredient; however, ingeneral, it is preferable to employ a dosage amount in the range of fromabout 250 mg to 1000 mg. In parenteral administration, the unit dosageis usually the pure compound I in sterile water solution or in the formof a soluble powder intended for solution.

The preferred method of administration of the Formula I antibacterialcompounds is parenteral by i.v. infusion, i.v. bolus, or i.m. injection.

For adults, 5-50 mg of Formula I antibacterial compounds per kg of bodyweight given 2, 3, or 4 times per day is preferred. Preferred dosage is250 mg to 1000 mg of the Formula I antibacterial given two (b.i.d.)three (t.i.d.) or four (q.i.d.) times per day. More specifically, formild infections, and particularly urinary tract infections, a dose of250 mg t.i.d. or q.i.d. is recommended. For moderate infections againsthighly susceptible gram positive and gram negative organisms, a dose of500 mg t.i.d. or q.i.d. is recommended. For severe, life-threateninginfections against organisms at the upper limits of sensitivity to theantibiotic, a dose of 1000 mg t.i.d. or q.i.d. is recommended.

For children, a dose of 5-25 mg/kg of body weight given 2, 3, or 4 timesper day is preferred; a dose of 10 mg/kg t.i.d. or q.i.d. is usuallyrecommended.

Antibacterial compounds of Formula I are of the broad class known ascarbapenems or 1-carbadethiapenems. Naturally occurring carbapenems aresusceptible to attack by a renal enzyme known as dehydropeptidase (DHP).This attack or degradation may reduce the efficacy of the carbapenemantibacterial agent. The compounds of the present invention, on theother hand, are significantly less subject to such attack, and thereforemay not require use of a DHP inhibitor. However, such use is optionaland contemplated to be a part of the present invention. Inhibitors ofDHP and their use with carbapenem antibacterial agents are disclosed inthe prior art [see European Patent Applications No. 79102616.4 filedJul. 24, 1979 (Patent No. 0 010 573); 79102615.6, filed Jul. 24, 1979(Patent No. 0 007 614); and No. 82107174.3, filed Aug. 9, 1982(Publication No. 0 072 014)].

The compounds of the present invention may, where DHP inhibition isdesired or necessary, be combined or used with the appropriate DHPinhibitor as described in the aforesaid patents and publishedapplication. Thus, to the extent that the cited European patentapplications 1.) define the procedure for determining DHP susceptibilityof the present carbapenems and 2.) disclose suitable inhibitors,combination compositions and methods of treatment, they are incorporatedherein by reference. A preferred weight ratio of Formula I compound:DHPinhibitor in the combination compositions is about 1:1. A preferred DHPinhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-acidor a useful salt thereof.

These combination compositions and their use are further embodiments ofthe present invention.

DETAILED DESCRIPTION OF THE INVENTION

The 2-(heterocyclylheteroaryliumalkyl)phenyl carbapenem compounds of thepresent invention may be prepared in accordance with well knownprocedures in the art. Particularly useful are the following syntheticschemes in which the various symbols employed are as defined above.##STR32##

The steps for preparing the 2-phenyl carbapenem intermediate are wellknown in the art and are explained in ample detail in U.S. Pat. Nos.4,260,627 and 4,543,257, which are incorporated herein by reference.Addition of the hetercyclylheteroaryliumalkyl moiety, generallyrepresented by the formula: ##STR33## is as represented in the schematicdiagram above.

The bridging element "A" is already in place when the phenyl groupbecomes a part of the carbapenem compound at the time of cyclization. Inthe preferred embodiments of the present invention, the bridging element"A" is simply alkyl. However, it is also an embodiment of the presentinvention to include a heteroatom in the alkyl chain, as defined furtherabove. Preparation of such a heteroatom-containing alkyl bridge is inaccordance with the following synthetic scheme: ##STR34##

The bridging element terminates in a hydroxyl group which is thenchanged to an active leaving group, e.g., iodide. Treatment with thedesired heterocyclylheteroaryl reactant directly provides theheterocyclylheteroaryliumalkylphenyl sidechain. More particularly, threealternative procedures may be utilized for addition of theheterocyclylheteroarylium group.

Activation of the Phenyl-A-OH Group

This step may be carried out in accordance with well-known procedures,some of which are exemplified in the following equations. ##STR35##

In words relative to the equations, the hydroxyl group may be convertedto a methanesulfonate group by treating with methanesulfonyl chloride inthe presence of triethylamine. A suitable solvent, e.g.,dichloromethane, is employed and the reaction is carried out at reducedtemperatures. In turn, the methanesulfonate intermediate may beconverted to the more reactive iodide derivative by treatment withsodium iodide in a suitable solvent, e.g., acetone, at reduced orambient temperatures. Alternatively, the hydroxyl group may be directlyconverted into the iodide group by common methods known in the art. Forexample, treatment of the hydroxyl group with methyltriphenoxyphosphonium iodide in a suitable solvent, such asdimethylformamide, at reduced or ambient temperatures, directly providesthe desired iodide. Further, the hydroxyl group may be converted intothe very reactive trifluoromethanesulfonate group. However, such anactivating group cannot be isolated by conventional techniques but maybe formed and used in situ. Thus, treatment of the hydroxyl group withtrifluoromethanesulfonic acid anhydride in the presence of, usually, thereacting heterocyclylheteroaromatic base in a suitable solvent, such asdichloromethane, at reduced temperatures provides for the in situgeneration of this activating group. Alternatively, thetrifluoromethanesulfonate group may be generated in situ from the iodidegroup by treatment with excess silver trifluoromethanesulfonate in asuitable solvent, e.g., acetonitrile, at reduced temperatures.

Once the desired activation has been carried out, introduction of theheterocyclylheteroarylium group can then proceed. One of the followingthree procedures has been found suitable for such introduction.

Method A

The activated group is iodide and the addition of theheterocyclylheteroarylium group, e.g., 4-N-thiamorpholinylpyridinium, isaccomplished simply by treating with the corresponding heteroaryl, e.g.,4-N-thiamorpholinylpyridine, in a suitable solvent, e.g., acetonitrile,at about room temperature.

Method B

The activating group is trifluoromethanesulfonate and is formed in situby treatment of the alcohol with trifluoromethanesulfonic acid anhydridein the presence of at least two equivalents of heterocyclylheteroaryl toprovide the corresponding heterocyclylheteroarylium in a suitablesolvent, e.g., dichloromethane, at reduced temperatures.

Method C

The activated group is trifluoromethanesulfonate which is formed in situby treatment of the iodide derivative with excess silvertrifluoromethanesulfonate in a suitable solvent, e.g., acetonitrile, atreduced temperatures. As with Method A, the heterocyclylheteroaryl toprovide the corresponding heterocyclylheteroarylium is simply added anddisplacement of the activating group then takes place directly.

Where the heterocyclylheteroarylium group has one or more substituentsR^(c) and R^(d), the most facile method of providing such a substituentis to employ as the reactant in the preparation methods described abovea heterocyclylheteroaryl compound which already has the desiredsubstituent(s). Such substituted heterocyclylheteroaryl compounds arereadily available starting materials or may be prepared in astraight-forward manner using known literature methods.

In the preparation methods described above, the carboxyl group at the3-position remains blocked by a carboxyl covering group until the finalproduct is prepared. Then, if the anionic carboxylate is desired so asto form the zwitterionic internal salt, deblocking may be carried out ina conventional manner, with care being taken to avoid a procedure whichis so harsh as to disrupt other portions of the final product molecule.

The general synthesis description above and the particularexemplifications which follow show the 6-(1-hydroxyethyl) moiety, whichis preferred in most cases. However, it has been found that with certain2-sidechain selections, the ultimate balance of favorable clinicalproperties in the overall molecule may be enhanced by selection of the6-(1-fluoroethyl) moiety instead. Preparation of this and other6-fluoroalkyl compounds within the scope of the present invention may becarried out in a straightforward manner using techniques well known inthe art of preparing carbapenem antibacterial compounds. See, e.g., J.G. deVries et al., Heterocycles, 23 (8), 1915 (1985); J6-0163- 882-A(Sanraku Ocean).

For all of the compounds exemplified herein, the R substituent ishydrogen, which is preferred. However, when R=methyl, the analogous6-(1-hydroxyethyl) and 6-(1-fluoroethyl)carbapenems of the presentinvention are prepared in the manner described herein utilizing theappropriately chosen synthons which are known in the art. See, forexample, L. M. Fuentes, I. Shinkai, and T. N. Salzmann, JACS, 108, 4675(1986); and BE-900-718-A (Sandoz) respectively.

EXAMPLE 1 ##STR36##

To a stirred solution of 42.7 mg (0.1 mmole) of 1 in 1 ml of sieve driedCH₂ Cl₂ at 0° C. under a nitrogen atmosphere was added sequentially 15.2mg (0.15 mmole) of neat Et₃ N and then 14.9 mg (0.13 mmole) of neatmesyl chloride. The resulting mixture was stirred for 15 minutes, andthen partitioned between EtOAc, ice-H₂ O, and some 2N HCl. The organicphase was separated, washed with saturated NaCl solution, dried over Na₂SO₄, filtered, evaporated, and dried in vacuo to give a quantitativeyield of 2; IR (CH₂ Cl₂): 1780, 1745, 1725 cm⁻¹ ; 200 MHz ¹ H-NMR(CDCl₃): δ 1.49 (d, J=6.4 Hz, CH₃ CH), 2.96 (s, CH₃ SO₃), 3.18 (dd,J=9.9, 18.1 Hz, H-1), 3.34 (dd, J:=8.9, 18.1 Hz, H-1), 3.43 (dd, J:=2.8,8.1 Hz, H-6), 4.30 (dt, J=2.3, 2.8, 9.9 Hz, H-5 ), 4.66 (m, CH₃ CHOH andCH₂ CH═CH₂), 5.26 (m, OCH₂ CH═CH₂), 5.29 (s, ArCH₂ OSO₂), 7.40 (s,Ar-H). UV: λ_(max) ^(p-diox) =314 nm.

EXAMPLE 2 ##STR37##

To a stirred solution of 38.8 mg (0.077 mmole) of 2 in 1 ml of acetoneat 0° C. was added all at once 23 mg (0.15 mole) of NaI. The ice-H₂ Obath was removed and the mixture stirred further under a nitrogenatmosphere for 0.5 hour. After this time, the resulting mixture waspartitioned between EtOAc, ice-H₂ O, 5% Na₂ S₂ O₄ (aq.) solution andsaturated NaCl solution. The organic phase was separated, dried over Na₂SO₄, filtered, evaporated and dried in vacuo to give 3; IR (CH₂ Cl₂):1780, 1745, 1725 cm⁻¹ ; 200 MHz ¹ H-NMR (CDCl₃): δ 1.49 (d, J=7.4 Hz,CH₃), 3.17 (dd, J=9.8, 18.1 Hz, H-1), 3.29 (dd, J=8.7, 18.1 Hz, H-1),3.41 (dd, J=2.9, 8.7 Hz, H-6), 4.27 (dt, J=2.9, 8.7, 9.8 Hz, H-5), 4.65(m, CH₃ CHOH and OCH₂ CH═CH₂), 5.26 (m, OCH₂ CH═CH₂), 5.89 (m, OCH₂CH═CH₂), 7.32 (m, Ar-H). UV: λ_(max) ^(p-diox) =322 nm.

EXAMPLE 3 ##STR38##

In 5 ml of sieve dried acetonitrile (CH₃ CN) there was dissolvedenantiomerically pure 2-(iodomethyl-4-phenyl)carbapenem (3.) (166.3 mg,0.310 mmole), and the solution was cooled to 0° C. There was then addedneat 4-pyrrolidinopyridine (4.) (52.8 mg, 0.356 mmole), after which thereaction mixture was stirred at room temperature for 1.5 hours, at theend of which time thin layer chromatography (TLC) with 5% ethyl acetatein dichloromethane showed no iodocarbapenem starting material remaining.The reaction mixture was concentrated in vacuo to give 222.1 mg of areddish thick oil. The material was used without further treatment inthe subsequent step of deblocking.

IR (CH₂ Cl₂): 1780, 1740, 1720, 1645 cm⁻¹ ; 200 MHz ¹ H-NMR (CDCl₃): δ1.49 (d. CH₃), 2.16 (m, NCH₂ CH₂), 3.18 (dd, H-1), 3.36 (dd, H-1), 3.48(dd, H-6), 3.56 (m, NCH₂ CH₂), 4.32 (dt, H-5), 4.69 ((m, OC₂ CH═CH₂ andCH₃ CHO), 5.30 (m, OCH₂ CH═CH₂) 5.63 (s, ArCH₂ N+), 5.92 (m, OCH₂CH═CH₂), 6.78 (d, pyridine H-3 and pyridine H-5), 7.42 (d, ArH), 7.53(d, ArH), 8.54 (d, pyridine H-2 and pyridine H-6).

EXAMPLE 4 ##STR39##

In 3 ml of dichloromethane and 2 ml of ethyl acetate there was dissolvedthe crude enantiomerically pure product of Example 3,2-(4-pyrrolidinopyridiniummethyl-4-phenyl)carbapenem (5.) (about 0.310mmole), and the solution was cooled under nitrogen atmosphere to 0° C. Asolid mixture of triphenylphosphine (24.4 mg, 0.093 mole) and tetrakistriphenylphosphinepalladium (35.8 mg, 0.031 mmole) was then added,followed by 2-ethylhexanoic acid (54.5 μl, 0.341 mmole) and 0.5Mpotassium 2-ethylhexanoate in ethyl acetate solution (682 μ1, 0.34mmole). The reaction mixture was then stirred for 4.0 hours at roomtemperature, after which time the reaction slurry was diluted withdiethyl ether and the solid product was collected by centrifugation. Thesupernatant was decanted and the solid residue was washed three timeswith diethyl ether, after which the product was dried under high vacuumto yield 198.5 mg of a reddish solid. The crude reaction product wasdissolved in a minimum volume of water, applied to three 500μ 20×20 cmsilica gel reverse phase chromatography plates, and eluted with 30%tetrahydrofuran in water. The product bands were extracted six timeswith a 4:1 mixture of acetonitrile:water and the combined aqueousextracts were washed three times with hexanes, after which the aqueoussolution was filtered through a prewashed DR Gelman millipore filter andconcentrated in vacuo, then lyophilized to give 84.6 mg of a slightlyyellow solid.

IR(nujol mull) 1744, 1650, 1600, 1660 cm⁻¹ ; 200 MHz ¹ H NMR (D₂ O): δ1.31 (d, J=6.5 Hz, CH₃). 2.07 (m, CH₂ CHCH₂ N, 3.03 (dd, J=10, 17 Hz,H-1), 3.43 (m, H-1), 3.49 (m, NCH₂ CH₂, and H-6), 4.29 (m, H-5 and CH₃CH), 5.27 (s, ArCH₂ N+), 6.73 (d, J=7.5 Hz, pyridine H-3 and pyridineH-5), 7.27 (d, J=8.3 Hz, Ar-H), 7.41 (d, J=8.3 Hz, Ar-H), 8.02 (d, J-7.5Hz, pyridine H-2 and pyridine H-6); UV λ_(max) ^(H).sbsp.2^(O) =298 nm.

EXAMPLES 5-7

Employing the procedures described above, additional compounds of thepresent invention were prepared. These are described in the table below,which additionally includes characterizing data and the method ofpreparation for each compound.

    ______________________________________                                         ##STR40##                                                                     Example No.                                                                            ##STR41##                                                                               ##STR42##                                                                               Method of Preparation                           ______________________________________                                                  ##STR43##                                                                              299       A                                                6                                                                                       ##STR44##                                                                              299       A                                                7                                                                                       ##STR45##                                                                              297       A                                                ______________________________________                                    

What is claimed is:
 1. A compound of the formula: ##STR46## wherein: Ris H or CH₃ ;R¹ and R² are independently H, CH₃ --, CH₃ CH₂ --, (CH₃)₂CH--, HOCH₂ --, CH₃ CH(OH)--, (CH₃)₂ C(OH)--, FCH₂ CH(OH)--, F₂CHCH(OH)--, F₃ CCH(OH)--, CH₃ CH(F)--, CH₃ CF₂ --, or (CH₃)₂ C(F)--;R^(a), R^(b), R^(c), and R^(d) are independently selected from the groupconsisting of (R^(c) represents from 1 to 3 substituents which may bethe same or different):a) a trifluoromethyl group: --CF₃ ; b) a halogenatom: --Br, --Cl, --F, or --I; c) C₁ -C₄ alkoxy radical: --OC₁₋₄ alkyl;d) a hydroxy group: --OH; e) (C₁ -C₆ alkyl) carbonyloxy radical:##STR47## alkyl; f) a carbamoyloxy radical which is unsubstituted orsubstituted on nitrogen with one or two C₁ -C₄ alkyl groups: ##STR48##where R^(y) and R^(z) are independently H or C₁₋₄ alkyl; g) a C₁ -C₆alkylthio radical, C₁ -C₆ alkylsulfinyl radical or C₁ -C₆ alkylsulfonylradical: ##STR49## alkyl where n=0-2, and the alkyl portion isoptionally substituted by cyano; h) a sulfamoyl group which isunsubstituted or substituted on nitrogen by one or two C₁ -C₄ alkylgroups: ##STR50## where R^(y) and R^(z) are as defined above; i) anamino group, or a mono (C₁ -C₄ alkyl) amino or di(C₁ -C₄ alkyl)-aminogroup: ##STR51## where R^(y) and R^(z) are as defined above; j) aformylamino group: ##STR52## k) (C₁ -C₆ alkyl)carbonylamino radical:##STR53## alkyl; l) a (C₁ -C₄ alkoxy) carbonylamino radical: ##STR54##alkyl; m) a ureido group in which the terminal nitrogen is unsubstitutedor substituted with one or two C₁ -C₄ alkyl groups: ##STR55## whereR^(y) and R^(z) are as defined above; n) a sulfonamido group: ##STR56##alkyl; o) a cyano group: --CN; p) a formyl or acetalized formyl radical:##STR57## q) (C₁ -₆ alkyl)carbonyl radical wherein the carbonyl is freeor acetalized: ##STR58## alkyl or ##STR59## alkyl; s) ahydroximinomethyl radical in which the oxygen or carbon atom isoptionally substituted by a C₁ -C₄ alkyl group: ##STR60## where R^(y)and R^(z) are as defined above; t) a (C₁ -C₆ alkoxy)carbonyl radical:##STR61## alkyl; u) a carbamoyl radical which is unsubstituted orsubstituted on nitrogen by one or two C₁ -C₄ alkyl groups: ##STR62##where R^(y) and R^(z) are as defined above; v) an N-hydroxycarbamoyl orN(C₁ -C₄ alkoxy)carbamoyl radical in which the nitrogen atom may beadditionally substituted by a C₁ -C₄ alkyl group: ##STR63## where R^(y)and R^(z) are as defined above; w) a thiocarbamoyl group: ##STR64## x)an amidino group ##STR65## where R⁵, R⁶ and R⁷ are independentlyhydrogen, C₁ -C₄ alkyl or wherein two of the alkyl groups together forma C₂ -C₆ alkylidene radical optionally interrupted by a heteroatom andjoined together to form a ring; y) a carboxamidino group ##STR66## whereR⁵, R⁶ and R⁷ are as defined above; z) a guanidinyl group where R⁶ in a)above is NR⁸ R⁹ and R⁸ and R⁹ are as defined for R⁵ through R⁷ above;aa) hydrogen; ab) C₂ -C₆ alkenyl radical; ac) an unsubstituted orsubstituted C₂ -C₆ alkynyl radical; ad) C₃ -C₇ cycloalkyl radical; ae)C₃ -C₇ cycloalkyl methyl radical; af) C₅ -C₇ cycloalkenyl radical; ag)phenyl; ah) C₁ -C₆ alkyl radical; ai) C₁ -C₄ alkyl monosubstituted byone of the substituents a)-ag) above; aj) an anionic function selectedfrom the group consisting of: phosphono [P═O(OM^(c))₂ ]; alkylphosphono{P═O(OM^(c))--[O(C₁ -C₄ alkyl)]}; alkylphosphinyl [P═O(OM^(c))--(C₁ -C₄alkyl)]; phosphoramido [P═O(OM^(c))N(R^(y))R^(z) and P═O(OM^(c))NHR^(x)]; sulfino (SO₂ M^(c)); sulfo (SO₃ M^(c)); acylsulfonamides selectedfrom the structures CONM^(c) SO₂ R^(x), CONM^(c) SO₂ N(R^(y))R^(z), SO₂NM^(c) CON(R^(y))R^(z) ; and SO₂ NM^(c) CN, where R^(x) is phenyl orheteroaryl, where heteroaryl is as defined below except that there is noquaternary nitrogen and attachment through nitrogen is optional, and thephenyl and heteroaryl are optionally mono-substituted by R^(q) ; M^(c)is hydrogen or an alkali metal; R^(y) and R^(z) are as defined above;where R^(q) is a member selected from the group consisting of --OH;--OCH₃ --; --CN; --C(O)NH₂ ; --OC(O)NH₂ ; --OC(O)N(CH₃)₂ ; --SO₂ NH₂ ;--SO₂ N(CH₃)₂ ; --SOCH₃ ; --F; --CF₃ ; tetrazolyl; and --COOM^(a), whereM^(a) is hydrogen, alkali metal, methyl or phenyl; A is para (p) or meta(m) with respect to the point of attachment of the phenyl ring to thecarbapenem nucleus, and is (CH₂)_(m) --Q--(CH₂)_(n), where m is 0 to 2and n is 1 or 2; and Q is a covalent bond; O; S; SO; SO₂ ; NH; or N(C₁-C₄ alkyl); ##STR67## is a monocyclic aromatic hydrocarbon group having5 or 6 ring atoms in which one of the carbon atoms has been replaced bya nitrogen atom and attachment of said group is by way of said nitrogenatom, and in which one additional carbon atom is optionally replaced bya heteroatom selected from O and S, and from 1 to 3 carbon atoms areoptionally replaced by a nitrogen heteroatom; and ##STR68## is amonocyclic aliphatic hydrocarbon group having 4 to 7 ring atoms in whichone of the carbon ring atoms is replaced by a nitrogen atom andattachment of said group is by way of said nitrogen atom to a carbon ofthe monocyclic aromatic hydrocarbon group described above, and one ofthe remaining carbon ring atoms is optionally replaced by a heteroatomselected from N, O and S; and wherein the substitutent R^(d), definedabove, is attached to one of the carbon atoms of the ring; and Y isselected from:i) COOH or a pharmaceutically acceptable ester thereof;ii) COOM wherein M is an alkali metal or other pharmaceuticallyacceptable salt; iii) COOM wherein M is a negative charge in the casewhere a permanent positive charge exists elsewhere in the molecule.
 2. Acompound according to claim 1 wherein R¹ /R² is H-- and R² /R¹ is CH₃CH(OH)--.
 3. A compound according to claim 1 wherein R¹ /R² is H-- andR² /R¹ is CH₃ CH(OH)--; and A is --CH₂ --.
 4. A compound according toclaim 1 wherein R¹ /R² is H-- and R² /R¹ is CH₃ CH(OH)--; A is --CH₂ --;and ##STR69## is selected from the group consisting of ##STR70## whereX=O, S, or NR^(e), where R^(e) =C₁₋₄ alkyl, CH₂ SO₃ ⁻, CH₂ CH₂ SO₃ ⁻, orCH₂ COR^(f), where R^(f) =OCH₃, OCH₂ -phenyl, NH₂, or O⁻ M⁺, where M⁺=Na⁺ or K⁺.
 5. A compound according to claim 1 wherein R¹ /R² is H-- andR² /R¹ is CH₃ CH(OH)--; A is ##STR71##
 6. A compound according to claim1 wherein R¹ /R² is H-- nd R² /R¹ is CH₃ CH(OH)--; A is ##STR72## isselected from ##STR73##
 7. A compound according to claim 1 wherein thecompound is selected from the group consisting of ##STR74## where R' isa negative charge ⁻, a pharmaceutically acceptable ester, oradditionally a readily removable carboxyl covering group which is not apharmaceutically acceptable ester.
 8. A pharmaceutical composition forantibacterial use comprising an antibacterially effective amount of acompound of claim 1 and a pharmaceutically acceptable carrier therefor.9. A method of treating bacterial infections in human or animal subjectsin need of such treatment comprising administering to such subject anantibacterially effective amount of a compound of claim
 1. 10. Thecombination of a compound of claim 1 and a DHP inhibitor.
 11. Thecombination of a compound of claim 7 and the DHP inhibitor7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoic acid.
 12. Apharmaceutical composition for antibacterial use comprising anantibacterially effective amount of a compound of claim 1, aninhibitorily effective amount of a DHP inhibitor, and, optionally, apharmaceutically acceptable carrier therefor.
 13. A pharmaceuticalcomposition according to claim 12 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid.
 14. A method of treating bacterial infections in human or animalsubjects in need of such treatment comprising coadministering to suchsubject an antibacterially effective amount of a compound of claim 1 andan inhibitorily effective amount of a DHP inhibitor.
 15. A methodaccording to claim 14 wherein the DHP inhibitor is7-(L-2-amino-2-carboxyethylthio)-2-(2,2-dimethylcyclopropanecarboxamide)-2-heptenoicacid.